L-Thyroxine bioavailability can also be compromised by the numerous
medications that R.T. is taking. Estrogen therapy can increase T4
increasing TBG to increase T4 binding.
1 Cholestyramine, colestipol, iron sulfate,
antacids, sucralfate, calcium preparations, particularly the carbonate salt, and
raloxifene can impair thyroid absorption if these medications are administered at the
71,126–133 Cholesterol-lowering agents (e.g., lovastatin) and phosphate
binders are also reported to interfere with thyroid absorption.
questioned about the time she takes her thyroid medication. She should be instructed
to take it on an empty stomach or at night,
73 and at least 12 hours apart from the
raloxifene and 4 hours apart from the iron, calcium, and
126–133Aluminum-containing products (i.e., antacids, sucralfate) should
be discontinued because separating the concurrent administration of T4 and her
aluminum-containing preparations does not consistently correct this interaction.
R.T. should be changed to an aluminum- and calcium-free antacid and, if necessary,
-receptor antagonist. Proton pump inhibitors (e.g., omeprazole) should be
avoided because decreased acid secretion may reduce T4 absorption, although data
135,136 After R.T. has been instructed on the proper times of
administration for her medications, the therapeutic response and thyroid function tests
should be reevaluated in 6 to 8 weeks before any changes are made.
CASE 52-9, QUESTION 2: Could R.T.’s hypothyroidism be responsible for her hypercholesterolemia?
Type IIa hypercholesterolemia is the most common lipid abnormality observed in
patients with primary hypothyroidism.
137 Although the rate of cholesterol synthesis is
normal in hypothyroid patients, the rate of cholesterol clearance is decreased.
Similarly, slow removal of triglycerides may result in hypertriglyceridemia.
Hypercholesterolemia is frequently observed before the appearance of clinical
hypothyroidism. Treatment with T4 alone should lower the cholesterol levels if no
other causes are contributing.
QUESTION 1: R.B., a 65-year-old, agitated woman arrived at the emergency department complaining of
and hypothyroidism. Although she has been advised repeatedly to take her T4
regularly, she continues to take it
drawn 4 months ago was 0.5 ng/dL (normal, 0.7–1.9). Haloperidol 2 mg IM and morphine
assessment of R.B.’s subjective and objective data?
R.B. has several symptoms consistent with myxedema coma.
features are hypothermia, delayed DTRs, and an altered sensorium that ranges from
stupor to coma. Other predominant features include hypoxia, carbon dioxide
retention, severe hypoglycemia, hyponatremia, and paranoid psychosis. Typical
physical findings (Table 52-3) include a puffy face and eyelids, a yellowish
discoloration of the skin, and loss of the lateral eyebrows. Pleural and pericardial
effusions and cardiomegaly may be present. Because myxedema coma frequently
occurs in older women, it is often difficult to distinguish the signs and symptoms from
dementia or other disease states, as illustrated by R.B. Precipitating factors include
cold weather or hypothermia, stress (e.g., surgery, infection, trauma), coexisting
disease states such as MI, diabetes, hypoglycemia, or fluid and electrolyte
abnormalities (especially hyponatremia), and medications such as sedatives, narcotic
analgesics, antidepressants, and other respiratory depressants and diuretics.
Haloperidol and morphine might be responsible for what appears to be impending
myxedema coma in R.B. In severely myxedematous patients, respiratory depressants
(anesthetics, narcotic analgesics, phenothiazines, sedative-hypnotics) alone or in
combination with the hypothermic effects of the phenothiazines can aggravate the
preexisting hypothermia and carbon dioxide retention to precipitate myxedema
138,139 Tranquilizers such as haloperidol should not be given; small doses of less
depressive sedative-hypnotics such as the benzodiazepines should be used only when
necessary. Myxedematous patients are also inherently sensitive to the respiratory
depressant effects of narcotic analgesics,
especially morphine. A dose as small as 10 mg may induce coma in a hypothyroid
patient or cause death in a patient who is already comatose. If morphine is required,
the dose should be decreased to one-third to one-half the usual analgesic dose, and
the respiratory rate should be monitored closely.
CASE 52-10, QUESTION 2: What would be a reasonable therapeutic plan for the management of R.B.’s
Emergency treatment, usually in the intensive care unit, of myxedema coma is
directed toward thyroid replacement, maintenance of vital functions, and elimination
of precipitating factors. Despite immediate and aggressive therapy with large
replacement doses of thyroid, mortality rates of 60% to 70% are common.
is the drug of choice in myxedema coma is controversial because
no comparative trials have been conducted. Although T3
cardiotoxic, it has been recommended because its more rapid onset might reverse
coma faster, and the peripheral conversion from T4
might be inhibited in severe systemic disease.
139–143 T4 alone, T3 alone, and a
combination of the two have all been used successfully to treat myxedema coma.
However, L-thyroxine is generally regarded as the hormone of choice because of
greater clinical experience with T4
. Also, mortality has occurred despite
levels achieved after T3 administration.
143 T3 might be considered after
failure of T4 or if concomitant systemic illness (e.g., heart failure) is likely to impair
. Supraphysiologic elevations in T3
administration but are not seen after IV T3
infusion. Factors associated with a higher
mortality 1 month after therapy include older age, cardiac complications, and T4
replacement ≥500 mcg/day or T3
L-Thyroxine 400 to 500 mcg should be given IV initially in patients <55 years of
age without cardiac disease to saturate empty TBG sites and raise the serum T4
138,144 This initial dose can be adjusted based on the patient’s weight
and other restrictive factors (e.g., age, cardiac disease). The initial T4 dosage for
R.B. should be reduced to 300 mcg/day to avoid worsening her angina. If the proper
dosage is given, consciousness, restoration of vital signs, and decreased TSH levels
should occur within 24 hours. If T3
is preferred, the usual dose is 10 to 20 mcg IV,
followed by 10 mcg every 4 hours for the first 24 hours, and then 10 mcg every 6
hours for a few days until oral therapy can be started.
Maintenance doses should be titrated to the patient’s clinical response. Because
myxedema can impair oral absorption, the IV route is preferred to ensure adequate
drug concentrations. Oral administration is permitted once GI function returns to
normal. The smallest dosage (without untoward effects) administered should be 50 to
100 mcg/day of T4 or 10 to 15 mcg of T3 every 12 hours.
Supportive measures include assisted ventilation, glucose for hypoglycemia,
restriction of fluids for hyponatremia, and the use of blood or plasma expanders to
prevent circulatory collapse and to maintain blood pressure. The use of blankets to
treat R.B.’s hypothermia is not advised because vasodilation will occur and further
compromise the cardiovascular components of shock. Although steroids have not
been shown to be clearly beneficial in primary myxedema, they may be lifesaving in
patients with hypopituitarism masquerading as myxedema coma. Because it is
difficult to distinguish between primary and secondary myxedema, hydrocortisone 50
to 100 mg every 6 hours should be given empirically.
Appropriate measures should be taken to relieve R.B.’s chest pain while ruling out
the possibility of an MI. The use of a narcotic antagonist such as naloxone may be
beneficial in this instance because it can reverse the effects of the morphine.
Naloxone can also arouse comatose patients intoxicated with alcohol.
Hypothyroidism with Congestive Heart Failure
QUESTION 1: E.B., a 45-year-old woman, is admitted with chest pain, SOB, dyspnea on exertion, and
Pertinent laboratory findings include the following results:
TSH, 100 microunits/mL (normal, 0.45–4.1)
Creatinine phosphokinase, 300 units/L with negative MB bands
Aspartate aminotransferase (AST), 80 units/L
Lactate dehydrogenase (LDH), 250 units/L
Brain natriuretic peptide, 550 pg/mL
Troponin, 0.3 ng/mL (normal, 0.3–1.5)
started. E.B.’s symptoms improve, but her cardiac abnormalities are not reversed.
Why do these clinical findings suggest hypothyroidism?
E.B.’s abnormal thyroid function tests, symptoms, physical findings, and history of
RAI therapy are consistent with severe hypothyroidism. “Myxedema heart” can be
confused with low-output CHF because the symptoms are similar: cardiomegaly,
dyspnea, edema, pericardial effusions, and abnormal ECG.
hypothyroidism should be ruled out in all patients with new or worsening symptoms
of cardiovascular disease (e.g., angina, arrhythmia). Although hypothyroidism alone
rarely causes CHF, it can worsen an underlying cardiac condition. Rarely,
ventricular arrhythmia, including torsades de pointes, can occur from a prolonged QT
Although E.B.’s enzyme elevations (i.e., AST, CK, LDH, CPK) are suggestive of
an MI, they all may be moderately or significantly increased from chronic skeletal or
cardiac muscle damage or from decreased enzyme clearance secondary to
hypothyroidism. The normal troponin level and negative CPK-MB bands eliminate
If E.B.’s cardiac abnormalities are caused by hypothyroidism, adequate doses of
T4 will restore the heart size, normalize the diastolic blood pressure, reverse the
ECG findings, and normalize the serum enzyme elevations within 2 to 4 weeks.
However, improvement in myocardial function begins only at dosages of 50 to 75
, which may be tolerated poorly by cardiac patients.
The relationship between the altered lipid metabolism of hypothyroidism and
increased risk of atherosclerosis is controversial and poorly documented.
rather uncommon among hypothyroid patients. Theoretically, the hypometabolic
state occurring in hypothyroidism may protect the ischemic myocardium by reducing
metabolic demands. However, hypothyroidism actually aggravates sub-endocardial
ischemia during an acute MI by decreasing erythrocyte production of 2,3-
diphosphoglycerate, which shifts the oxyhemoglobin dissociation curve to the left.
This effect further diminishes oxygen delivery to already ischemic tissues. Angina or
premature beats can develop or worsen with the institution of T4
doses should be titrated carefully (see Case 52-11, Question 3). Without organic
disease, digitalis is ineffective and may even be harmful. Hypothyroid patients show
an increased sensitivity to digitalis, and digitalis toxicity is possible unless the
maintenance dose is decreased (see Case 52-14, Question 3).
precipitate hypotension and/or syncope in hypothyroid patients because these patients
have a low circulating blood volume and their response to vasodilation can be
exaggerated. Furthermore, if β-blockers are required, the cardioselective β-blockers
are preferred. The non-cardioselective β-blockers have produced coronary spasm by
exacerbating the compensatory increase in norepinephrine levels and α-adrenergic
E.B. who has angina? What is the hormone replacement of choice in patients with cardiac disease?
Patients with long-standing hypothyroidism, arteriosclerotic cardiac disease, or
advanced age tend to be extremely sensitive to the cardiac effects of thyroid
hormone. Initiation of normal or even subtherapeutic doses might produce severe
angina, MI, supra- and ventricular premature beats, cardiac failure, or sudden death
and underscore the need to replace thyroid cautiously, and sometimes suboptimally,
The angina and cardiac status should be controlled before initiating T4
the patient with poorly controlled angina, cardiac catheterization is warranted to
assess the coronary artery status before starting hormone therapy. Coronary bypass
has been performed safely with minimal complications in the hypothyroid patient to
control the angina and may allow institution of full replacement doses without
For E.B., 12.5 to 25 mcg daily of T4 should be initiated cautiously and increased
as tolerated by similar increments of T4 every 4 to 6 weeks until a therapeutic dosage
is reached. The rapidity with which the increments can proceed is determined by
how well each increased dose is tolerated. If cardiac toxicity occurs, therapy should
be stopped immediately. Once symptoms resolve, therapy can be restarted using
smaller dosage increments and longer intervals between dosage adjustments. If
cardiac symptoms recur, further T4
therapy should be stopped pending cardiac
evaluation. In patients with severe cardiac sensitivity, complete euthyroidism might
never be achieved, and the correct replacement dosage is a compromise between
prevention of myxedema and avoidance of cardiac toxicity.
and ECG should be monitored closely during the titration period. T4 should be
discontinued or decreased at the first sign of cardiac deterioration. It is not necessary
to monitor thyroid function tests (e.g., TSH or FT4
because the results will remain low until adequate replacement is achieved. Thyroid
function tests should be obtained once maximally tolerated or estimated euthyroid
is the agent of choice in patients with cardiac abnormalities
because of its shorter duration of action. After therapy is withdrawn, the effects of T3
dissipate in 3 to 5 days, compared to 7 to 10 for T4
. Thus, if toxicity occurs, the
effects of T3 will disappear rapidly on cessation of therapy, a theoretical advantage
in the cardiac patient. Nevertheless, T3
is not recommended because its greater
potency requires finer and more difficult dosage titration to ensure smooth and
uniform blood levels. Furthermore, the high serum T3
administration might cause more cardiac toxicity, especially angina.
QUESTION 1: M.P., a healthy 53-year-old woman, comes in for her regular checkup. She denies any
of 1.2 ng/dL (normal, 0.8–1.4) and a TSH of 8 microunits/mL (normal, 0.45–4.1).
Does M.P. require thyroid treatment, based on her clinical presentation and laboratory findings?
M.P.’s free thyroid levels are normal, but her TSH level is elevated, indicating
subclinical hypothyroidism (SH). The prevalence of SH ranges from 4% to 10% and
increases to 26% in the elderly population, particularly women.
whether SH represents the early stages of thyroid failure. The estimated risk of
developing overt hypothyroidism after 10 years in untreated patients by Kaplan–
Meier curves was 0% for a TSH level of 4 to 6 microunits/mL, 42.8% for a TSH
level of 6 to 12 microunits/mL, and 76.9% for a TSH level >12 microunits/mL. This
risk increased in patients with positive thyroid antibodies.
common clinical scenarios involve asymptomatic patients with TSH levels <10
microunits/mL, negative thyroid antibodies, and no history of prior thyroid disease,
routine thyroid screening has been recommended, particularly in elderly women.
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